Adverse drug reactions (ADRs) are a major clinical problem. According to a widely cited meta-analysis, ADRs was ranked between the fourth and sixth most common cause of death (Lazarou et al., 1998). In particular, potentially serious cutaneous ADRs account for about 2-3% of all hospital admissions (Bigby et al., 1986). Although drug eruptions may be mild to moderate, such as maculopapular rash, erythema multiforme (EM), urticaria, and fixed drug eruption, more severe cutaneous ADRs are life-threatening and frequently result in death, such as Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN; Lyell's syndrome).
SJS is characterized by high fever, malaise, and a rapidly developing blistering exanthema of macules and target-like lesions accompanied by mucosal involvement. TEN has similar presentations with an even more extensive skin detachment and a higher mortality rate (30 to 40%). Although the incidence of SJS/TEN is rare with an annual estimated incidence of 3-5 per million people, these conditions can kill or severely disable previously otherwise healthy people (Roujeau and Stern, 1994). The severity of the condition has prompted pharmaceutical companies to withdraw a few newly released drugs.
Almost all SJS/TEN cases are caused by drugs, most commonly sulfonamides, anticonvulsants, allopurinol, nonsteroidal anti-inflammatory drugs (NSAIDs), and antimalarials (Roujeau et al., 1995). In Taiwan, anticonvulsants (carbamazepine, phenyloin and phenobarbital), and allopurinol are the most common drugs causing SJS/TEN. Other medications such as NSAID and antibiotics are also noted to cause severe ADR.
Recent developments of pharmacogenomics have implied that the susceptibility to ADRs is associated with genetic variants. A successful example of application of pharmacogenomic study to prevent drug-induced side effect is genotyping thiopurine methyltransferase (TPMT) before prescribing azathioprine, a drug for rheumatologic or cancer diseases (Yates et al., 1997). An individual's genomic polymorphism(s) of TPMT can cause enzyme deficiency and slow metabolizing rate, resulting in leukocytopenia. This kind of molecular diagnostics certified by CLIA (Clinical Laboratory Improvement Amendments) is now offered by reference laboratories in the USA (Prometheus Laboratory Inc.; Genaissance Pharmaceutical) and Europe. Although susceptibility to SJS/TEN on certain drugs is thought to be genetically determined (Gennis M A, 1991; Edwards S G, 1999), the responsible genetic factors have yet to be identified and currently there is no method clinically useful that can be used to predict who will develop SJS/TEN or to which drugs.